The system is designed, in part, to address a problem of significant resources being spent on monitoring patients, or clinical drug study enrollees, in person to ensure they take a drug dosage and take it according to the appropriate dosing regimen. Certain pharmaceuticals, such as antibiotics and treatments for tuberculosis, HIV, and malaria, must be administered according to a strict dosing regimen to ensure that the patient is properly treated, does not skip individual dosings or ceases treatment early. Besides the danger of the condition re-emerging following premature termination of treatment, certain bacterial and viral strains may become treatment resistant if the full treatment course is not followed or is not followed according to the dosage regimen.
Of course, the need to ensure patients take their medication is not limited to treating conditions in which development of a drug resistance organism is a concern. The clinic may be spending extra resources to ensure patient compliance with the dosing regimen solely to ensure that patients recover. Those resources could be better spent on medications if the clinic knows which patients take the medication and which patients do not.
To address these concerns, a significant amount of the public health money spent worldwide is not spent on the medicines themselves but instead is directed to efforts to ensure compliance with the dosing regimen. One of these methods is directly observed therapy (DOT), in which the patient visits the clinic to be administered the medicine under direct observation of the health care provider. Alternatively, the health care provider travels to the patient to directly observe administration of the medicine to the patient. In either situation, there is a waste of resources: either the patient is wasting resources traveling to a clinic on a periodic basis to ensure that someone observes that they are taking the medicine, or a health care provider is wasting resources traveling to the patient to directly observe the patient taking the medicine. For many patients who live in rural areas of developing nations, traveling to a health care provider can be very difficult, as many rural areas do not have a health care provider nearby, most people who are poor can cannot afford to own a car, and public transport is often unreliable or impacted by weather conditions or other factors beyond the control of the patient. These same factors also impact the ability of a health care provider to visit individual patients, but in addition, each health care provider may have numerous patients who are in geographically disparate locations. This situation limits the number of patients a single health care provider can monitor in person to ensure the patient complies with a drug dosage regimen.
This waste in resources is even more egregious because the group of patients who takes the medicine in the appropriate manner is treated the same as the group of patients that regularly fails to take the medication in the appropriate manner. Both groups are required to be directly observed by the health care provider. The inventor has determined that significant resources can be redirected from observing patients to instead providing medicines to treat patients if patients who comply with the dosing regimen are permitted to self-administer the medicine. The inventor has developed pharmaceutical compositions and methods to determine whether or not a patient is taking the medicine.
The compositions and methods disclosed herein also may be useful in clinical drug studies to determine whether or not a study subject is taking the study drug in the clinical study. In a clinical study, drug efficacy will be determined from the outcomes of the study, which makes the ability to determine if a study enrollee has taken the study drug according to the dosing schedule critical for determining the success or failure of a new drug. If the study enrollees do not take the drug or do not take it according to the dosing regimen, the drug may not be effective in treating the condition, or results from the study may not accurately reflect the true efficacy of the drug being studied. For example, if the results of a study include too many enrollees who failed to comply with the drug dosing regimen, statistically significant results of the study may not be attained, and the resulting outcome may provide only a marginal benefit to the company's objective because the results provide limited value in assessing the drug's safety and effectiveness. In addition, studies with results based on a low number of study enrollees may cause regulatory authorities (such as the FDA) to require additional studies or make negative inferences about the outcome, both of which add cost to and may delay the approval of the product—a significant negative financial result for the company.
There are a number of compliance systems and dosage forms in the prior art. For example, U.S. Pat. No. 7,062,312 discloses an orally administrable medication composition that includes a visual marker. When the medication is orally ingested, the marker causes a coloration or discoloration of the oral and/or pharyngeal cavity of a subject. By visually observing the oral and/or pharyngeal cavity of the subject, one can determine whether medication has been ingested based upon the presence or absence of the coloration/discoloration. The '312 patent further explains that noncompliance is addressed by notifying the patient that compliance is being monitored and that should noncompliance persist, that information would allow a caregiver to alter the methods of medication delivery. For example, a child in school or daycare who requires daytime dosing of an antibiotic for recurrent ear infections could be given an antibiotic containing the marker. The child could then be checked for ingestion compliance immediately after scheduled ingestion, or if necessary, several hours after the scheduled ingestion. The verification could occur, for example, by visual inspection of the oral and/or pharyngeal cavity immediately after the delivery under natural light or several hours later by inspection under a light which causes fluorescence.
U.S. Pat. No. 6,068,981 is directed to a method of monitoring a therapeutic regimen in an animal. The method involves: a) providing to the animal a therapeutic compound and a detectable compound that passes into the bloodstream, excretory system, or other tissue or body fluid in detectable form; b) after a period of time, following step (a), sufficient for passage of a detectable amount of the detectable compound into the body fluid or tissue, collecting a sample of the fluid or tissue from the animal; and c) measuring or detecting the detectable compound, or a detectable metabolite thereof, in the sample, wherein the detectable compound involves one member of a specific binding pair, and detection is carried out using the second member of the specific binding pair.
U.S. Pat. No. 5,908,788 is directed to a method of monitoring compliance of a patient that has been placed on a medication maintenance program with a prescribed medication dosage by determining a normalized urine methadone concentration. According to the method, an unadulterated urine sample is obtained from the patient. The urine methadone concentration and urine specific gravity are measured. The normalized urine medication concentration is calculated as a function of the measured medication concentration in the urine and the urine specific gravity. The calculated normalized urine medication concentration is compared with an expected medication concentration value for the patient for the maintenance program prescribed to determine any significant differences therebetween as an indication of noncompliance. Alternatively, a urinary-parameter normalized urine medication concentration is calculated as a function of the measured medication concentration in the urine, the urine specific gravity and at least one selected pharmacokinetic parameter of the medication. The calculated urinary-parameter normalized urine medication concentration is compared with an expected medication concentration value for an average compliant patient for the maintenance program prescribed to determine any significant differences therebetween as an indication of noncompliance.
U.S. Pat. No. 5,776,783 is directed to a method of monitoring therapeutic agent consumption. The method includes quantitative compliance markers and associated methods for monitoring patient compliance with medication prescriptions associated with compliance markers to eliminate the need for specific quantitative relationships for each new drug tested. According to the method of monitoring compliance of a patient who has been placed on a medication maintenance program with a prescribed medication dosage, the method includes (a) physically associating a compliance marker with a prescribed medication dosage prior to ingestion, (b) obtaining a sample of the patient's urine, (c) measuring the concentration of the compliance marker and its metabolites in the urine and the urine specific gravity, (d) calculating a normalized urine compliance marker and its metabolite concentration as a function of the measured compliance marker and its metabolite concentration in the urine and the urine specific gravity adjusted to account for the difference between the urine measured specific gravity and a preselected reference urine specific gravity, and (e) comparing the normalized urine compliance marker and its metabolite concentration with an expected normalized urine compliance marker and its metabolite concentration for the amount of compliance marker prescribed, as an indication of compliance or non-compliance.
U.S. Pat. No. 6,421,650 is directed to a medication management system which includes three components to assist a patient to control, monitor and manage administration of prescribed medications. The system includes a patient component having a retrievable patient database of patient medical history, prior prescribed medications and current prescribed medications, and it includes a data transfer interface, e.g., a hardwired interface, such as an RS232 interface or infrared data transfer port. The system also includes a physician component having a retrievable physician's database of medication information and an input/output device enabling a prescribing physician to enter prescription information into the physician component. The physician's database is capable of receiving and storing patient data transferred from the patient component through said data transfer interface. The system finally also includes a pharmacist component resident on a pharmacist's computer. The pharmacist's computer is adapted to interface with the patient component to transfer prescription data to said pharmacist component. At least one of each of the physician component and the pharmacist component has the capability of searching a medication database to determine potential medication interactions with currently prescribed medications and identify those to the physician or pharmacist for selective downloading to the patient component so that the patient can be alerted to the potential interactions. The patient component has a scheduler which tracks a plurality of medication dose schedules and includes alarm functions to prompt a patient to take particular medications, reschedule them, and alert the patient to potential interactions between medications and/or provide caution information to the patient for administration of the medication.
U.S. Pat. No. 6,578,003 is directed to a method and apparatus for improving patient compliance with prescriptions that utilizes computer terminals to convert prescription information into electronic form as records for each patient. Each such patient record includes information about the patient from the prescription and the prescription itself. In addition, demographic information about the patient is obtained from other commercial databases and added to the patient record. Then a regression analysis is run on the patient records using the various data elements versus the compliance of the patient with the prescription to determine the relative importance of each variable in the prediction. The analysis is used to segregate the patients into demographic clusters and to associate champion intervention messages with each cluster. When a patient's prescription is entered in the system thereafter, the model is used to associate the patient with a cluster and to direct the champion message to that patient. Further, a regression analysis may be run on the patient data to create a model of likelihood of prescription compliance in general by the patient. The result is a probability equation that allows a score to be assigned to each record. Based on this score, the patients most likely to fail to comply with their prescription are sent the champion interventions. As new challenge interventions messages are created additional information is gathered and the regression analysis is re-run. If the challenge message is more successful, it is substituted as the new champion message. The results of these interventions are recorded and appended to the related patient record.
U.S. Pat. No. 7,415,447 is directed to an apparatus and method for prediction and management of participant compliance in clinical research. The system uses empirically derived algorithms to generate decision rules to determine participant noncompliance and fraud with research protocols in clinical trials allows for the identification of complex patterns of variables that detect or predict participant noncompliance and fraud with research protocol, including performance and enrollment goals, in the clinical trial. The data may be used to overall predict the performance of any participant in a clinical trial, allowing selection of participants that tend to produce useful, high-quality results. The present invention can also be used to monitor participant compliance with the research protocol and goals to determine preferred actions to be performed. Optionally, the invention may provide a spectrum of noncompliance, from minor noncompliance needing only corrective feedback, to significant noncompliance requiring participant removal from the clinical trial or from future clinical trials. The algorithms and decision rules can also be domain-specific, such as detecting non-compliance or fraud among subjects in a cardiovascular drug trial, or demographically specific, such as taking into account gender, age or location, which provides for algorithms and decision rules to be optimized for the specific sample of participants being studied.
U.S. Pat. No. 6,039,688 is directed to a therapeutic behavior modification program with a compliance monitoring and feedback system. The therapeutic behavior modification program, compliance monitoring and feedback system includes a server-based relational database and one or more microprocessors electronically coupled to the server. The system enables development of a therapeutic behavior modification program having a series of milestones for an individual to achieve lifestyle changes necessary to maintain his or her health or recover from ailments or medical procedures. The program may be modified by a physician or trained case advisor prior to implementation. The system monitors the individual's compliance with the program by prompting the individual to enter health-related data, correlating the individual's entered data with the milestones in the behavior modification program and generating compliance data indicative of the individual's progress toward achievement of the program milestones. The system also includes an integrated system of graphical system interfaces for motivating the individual to comply with the program. Through the interfaces, the individual can access the database to review the compliance data and obtain health information from a remote source such as selected sites on the Internet. The system also provides an electronic calendar integrated with the behavior modification program for signaling the individual to take action pursuant to the behavior modification program in which the calendar accesses the relational database and integrates requirements of the program with the individual's daily schedule, and an electronic journal for enabling the individual to enter personal health-related information into the system on a regular basis. In addition, the system includes an electronic meeting room for linking the individual to a plurality of other individuals having related behavior modification programs for facilitating group peer support sessions for compliance with the program. The system enables motivational media presentations to be made to the individuals in the electronic meeting room as part of the group support session to facilitate interactive group discussion about the presentations. The entire system is designed around a community of support motif including a graphical electronic navigator operable by the individual to control the microprocessor for accessing different parts of the system.
US 2005/0267356 is directed to packages of medications that have features for improving patient compliance with taking the medication. According to the abstract of the published application, the method involve generating and storing an identifier for a specific dosage instance of a specific patient, and creating a package that includes a mechanism for conveying the identifier. Once the package is created, a set of one or more medications that are prescribed to be taken by the specific patient at the specific dosage instance are placed in the package. The set of medications are placed within the package in a manner that prevents the identifier from being perceived from the mechanism until the package is opened. Once opened, the identifier is perceived and communicated back to an automated compliance system.
Although these systems describe various systems for detecting whether or not a patient has taken a pharmaceutical, the system require direct observation and therefore does not alleviate the problem of wasted resources spent in monitoring patient compliance. Further, the systems are complicated and do not provide a simple method that is easily implemented to determine compliance with a drug dosing regimen. Further, because the patient can easily discern the result of the compliance determination, they can also easily provide a false report of compliance that is indistinguishable from a true report.